The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has an array of pharmacological and physiological roles within the central nervous system (CNS) and in the periphery, mediated by its interactions with a total of 14 structurally and pharmacologically distinct receptor subtypes. These receptors have been assigned to one of seven families, 5-HT1-7. The 5-HT7 receptor (5-HT7R) is the most recent addition to the 5-HT receptor family, and was cloned for the first time in 1993 from rat and mouse. Since then, it has been cloned from other species such as human, guinea-pig, and pig. The 5-HT7R was shown to be positively coupled to adenylyl cyclase via Gs proteins. It displays a low degree of homology (40%) with other Gs-coupled 5-HT receptors. Four different isoforms have been found, namely 5-HT7a, 5-HT7b, 5-HT7c, 5-HT7d. Only two isoforms (5-HT7a and 5-HT7b) are present in both rat and human, whereas the 5-HT7c receptor is found exclusively in rat, while the 5-HT7d is found only in human. Each of the isoforms appears to form a functionally active receptor with the 5-HT7a, being the most abundant (80%) in both rat and human brain. There appear to be no pharmacological differences among the four isoforms. High concentrations of the 5-HT7R have been detected by in situ hybridization and 5-HT7-like immunoreactivity in the hypothalamus, entorhinal cortex, septal areas, substantia nigra, amygdala, rapes nuclei and the trigeminal nucleus. In addition, moderate levels of 5-HT7-like immunoreactivity were found in the thalamus, hippocampus, cingulate and occipital cortex, caudate, putamen, and suprachiasmatic nucleus (SCN) of the rat. This distribution correlates well with distribution of mRNA encoding 5-HT7R protein. In fact, the 5-HT7R mRNA has been detected in thalamus, hypothalamus, hippocampus, amygdala, cortex, septum, and suprachiasmatic nucleus.
The potential of therapeutic effects of 5-HT7 agents have been hypothesized on the basis of such anatomical distribution. The link between 5-HT7Rs and the SCN suggests a potential role in circadian rhythms and sleep disorders. Lovenberg et al. (Lovenberg, T. W., Baron, B. M., de Lecea, L., Miller, J. D., Prosser, R. A., Rea, M. A., Foye, P. E., Racke, M., Slone, A. L., Siegel, B. W., Danielson, P. E., Sutcliffe, J. G., Erlander, M. G. Neuron 1993, 11, 449-458) demonstrated that phase advances in circadian neuronal activity of the SCN could be elicited using serotonergic ligands that display a pharmacological profile consistent with that of the 5-HT7R. Since then, 5-HT7Rs have been shown to be present in postsynaptic areas in the SCN where serotonergic neurones are proposed to play a key role in modulating circadian activity. Mullins et al.( Mullins, U. L.; Gianutsos, G.; Eison, A. S. Neuropsychopharmacol. 1999, 21, 352-367.) have supplied supporting evidence that implicates a possible role for 5-HT7R in depression. They demonstrated that antidepressant-induced expression of the immediate early gene, c-Fos, in the SCN was blocked by ritanserin (a high-affinity, but non-selective, 5-HT7R antagonist), but not by the 5-HT1A antagonist pindolol or the 5-HT1D antagonist sumatriptan. This suggests that the effect is mediated through 5-HT7Rs, although, with such non-selective antagonists, the involvement of other 5-HT receptors cannot be ruled out.
The involvement of the 5-HT7R in migraine pathogenesis has been proposed by Terron (Terron, J. A. Eur. J. Pharmacol. 2002, 439, 1-11) because the 5-HT7R-mediated vasodilator mechanism operates in vascular structures that have been implicated in migraine, such as the middle cerebral and external carotid arteries. Finally, several compounds possessing high 5-HT7R affinity have therapeutic indications as antipsychotic drugs and this has suggested that 5-HT7R may mediate therapeutic action of such compounds (Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.; Monsma, F. J. Jr.; Shen, Y.; Meltzer, H. Y.; Sibley, D. R. J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410).
It is therefore clear that the 5-HT7R may be a valuable drug target. During the last decade considerable research efforts have been directed towards the identification of selective 5-HT7R antagonists, (Leopoldo, M. Curr. Med. Chem. 2004, 11, 629-661) allowing the identification of some interesting compounds such as SB-258719, SB-269970, SB-656104, DR4004, LY215840, the chemical structures of which are depicted in FIG. 1.
However, these promising compounds present several limitations because of their low potency (SB-258719), modest selectivity (SB-656104, LY215840), and low metabolic stability (SB-269970, DR4004).
Therefore, the scope of the present invention is that of providing novel selectively-acting 5-HT7R ligands as useful pharmacological tools or potential drugs.
It is noteworthy that most 5-HT7R ligands reported to date act as antagonists, whereas a very limited number of agonists has been reported.
Of the different chemical classes which bind to 5-HT7Rs, arylpiperazines, four species of which are depicted and numbered in FIG. 2, have received our attention as well as that of other authors. Recently, we have reported structure affinity relationship studies of two distinct classes of 5-HT7R ligands, based on the structure of 1-arylpiperazine. Examples of these classes are represented by compounds 3 and 4 (Perrone, R., Berardi, F., Colabufo, N. A., Lacivita, E., Leopoldo, M., Tortorella, V. J. Med. Chem. 2003, 46, 646-649; Leopoldo, M.; Berardi, F.; Colabufo, N. A.; Contino, M.; Lacivita, L.; Perrone, R.; Tortorella, V. J. Pharm. Pharmacol. 2004, 56, 247-255).
In the present study, we screened the 1-(2-methoxyphenyl) piperazine derivatives 5-7, previously prepared in our laboratory as 5-HT1A ligands (Perrone, et al. J. Med. Chem. 1996, 39, 3195-3202.
Perrone, R. et al. J. Med. Chem. 1998, 41, 4903-4909) against the cloned rat 5-HT7R because they share some structural features with derivatives 1 and 2. We found that the compounds 6 and 7 possessed moderate affinities for 5-HT7R, as well as for 5-HT1A receptor.